title: Chronic over-expression of TGFβ1 alters hippocampal structure and causes learning deficits.
abstract: The cytokine transforming growth factor β1 (TGFβ1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. Although previous studies have shown that TGFβ1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFβ1 in isolation, we used transgenic mice that over-express a constitutively active porcine TGFβ1 in astrocytes. We found that TGFβ1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG microstructure and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFβ1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFβ1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning.
authors.affiliation: Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Alonso
authors.initials: A
authors.lastname: Martinez-Canabal
authors.forename: Anne L
authors.initials: AL
authors.lastname: Wheeler
authors.forename: Dani
authors.initials: D
authors.lastname: Sarkis
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
authors.forename: Wei-Yang
authors.initials: WY
authors.lastname: Lu
authors.forename: Marion S
authors.initials: MS
authors.lastname: Buckwalter
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.forename: Sheena A
authors.initials: SA
authors.lastname: Josselyn
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
mesh_terms: D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D019394:Ki-67 Antigen / Q000378:metabolism; D007859:Learning Disabilities / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D011930:Reaction Time / Q000235:genetics; D013028:Space Perception / Q000502:physiology*; D013552:Swine; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D053773:Transforming Growth Factor beta1
keywords: cytokine; dentate gyrus; hippocampus; learning; neurodegenerative disease